Sex Differences in Glomerular Lesions, in Atherosclerosis Progression, and in the Response to Angiotensin-Converting Enzyme Inhibitors in the ApoE-/- Mice Model.

This study analyzes sex-based differences in renal structure and the response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Eight weeks old ApoE-/- mice received enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. Each group consisted of six males and six females. Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells, and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in the female group), and hypertrophy of the PECs in males. This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Parenteral Nutrition in the Pediatric Oncologic Population: Are There Any Sex Differences?

Gender-based medicine is attracting increasing interest every day, but studies on pediatric populations are still limited. In this setting, sex differences among patients undergoing total parenteral nutrition (TPN) have not been previously reported. This study investigated the presence of sex differences in parenteral nutrition composition and outcomes among a cohort of pediatric patients admitted at the Oncohematology and Bone Marrow Transplant Unit of the Institute for Maternal and Child Health "Burlo Garofolo" of Trieste, Italy. For all 145 recruited patients (87 males, 58 females), the following data were collected: age, sex, volume and duration of TPN, macro- and micronutrient composition of TPN bags, electrolytic or blood gases imbalance, glycolipid alterations, liver damage during TPN, and the incidence of sepsis and thrombosis. The analysis showed that females required higher daily phosphate intake (p = 0.054) and essential amino acid supplementation (p = 0.07), while males had a higher incidence of hypertriglyceridemia (p < 0.05) and cholestasis. A higher incidence of sepsis was found in the non-transplanted male population (p < 0.05). No significant differences were appreciable in other analyzed variables. This study aims to create a basis for future gender-based nutritional recommendations in the pediatric field.

Sex-biased gene and microRNA expression in the developing mouse brain is associated with neurodevelopmental functions and neurological phenotypes.

BACKGROUND: Sex differences pose a challenge and an opportunity in biomedical research. Understanding how sex chromosomes and hormones affect disease-causing mechanisms will shed light on the mechanisms underlying predominantly idiopathic sex-biased neurodevelopmental disorders such as ADHD, schizophrenia, and autism. Gene expression is a crucial conduit for the influence of sex on developmental processes; therefore, this study focused on sex differences in gene expression and the regulation of gene expression. The increasing interest in microRNAs (miRNAs), small, non-coding RNAs, for their contribution to normal and pathological neurodevelopment prompted us to test how miRNA expression differs between the sexes in the developing brain. METHODS: High-throughput sequencing approaches were used to identify transcripts, including miRNAs, that showed significantly different expression between male and female brains on day 15.5 of development (E15.5). RESULTS: Robust sex differences were identified for some genes and miRNAs, confirming the influence of biological sex on RNA. Many miRNAs that exhibit the greatest differences between males and females have established roles in neurodevelopment, implying that sex-biased expression may drive sex differences in developmental processes. In addition to highlighting sex differences for individual miRNAs, gene ontology analysis suggested several broad categories in which sex-biased RNAs might act to establish sex differences in the embryonic mouse brain. Finally, mining publicly available SNP data indicated that some sex-biased miRNAs reside near the genomic regions associated with neurodevelopmental disorders. CONCLUSIONS: Together, these findings reinforce the importance of cataloguing sex differences in molecular biology research and highlight genes, miRNAs, and pathways of interest that may be important for sexual differentiation in the mouse and possibly the human brain.

In biomedical research, understanding the differences between males and females is essential for understanding diseases that affect one sex more than the other. This study focused on gene expression and regulation differences between male and female mouse brains during development. We found that many microRNAs, small molecules that play a role in development were expressed differently between male and female brains. These differences could be important in understanding why males and females develop differently, particularly regarding neurodevelopmental disorders like ADHD, schizophrenia, and autism. We also found that some microRNAs that differed between males and females were located near genes associated with these disorders. Overall, the study highlights the importance of understanding sex differences in molecular biology research and provides insights into potential genes and pathways of interest for further study.

Sex differences in children operated with pyeloplasty for pelvoureteric junction obstruction.

PURPOSE: Pelvoureteric junction obstruction (UPJO) is a common cause of hydronephrosis in children but no previous studies have evaluated differences between boys and girls operated with pyeloplasty. This study aimed to evaluate potential differences between sexes in children operated with pyeloplasty for PUJO in terms of presentation, surgery, and long-term results. METHODS: Data was retrospectively collected from all children operated on with pyeloplasty between January 2002 and December 2020. Data contained several variables covering presentation, surgery, and long-term results. RESULTS: In total, 194 patients were included of which 126 (64.9%) were boys. There were no significant differences in prenatal findings, pelvic dilation on ultrasound, function of the affected kidney, surgical method, obstruction type, resolution of hydronephrosis, or improvement of function. Boys presented with pain more often than girls (47.4 vs 25.0%, p < 0.01) while girls were more prone to infections preoperatively (17.2 vs 7.0%, p = 0.04). All nine patients requiring reoperation were boys (p = 0.03). CONCLUSION: Girls with UPJO seem to experience infections as presenting symptoms more often than boys, while boys significantly more often present with pain. There is also a higher percentage of boys needing reoperation.

Genetically predicted waist-to-hip circumference ratio and coronary artery disease: A sex-specific Mendelian randomization study.

Coronary artery disease (CAD) affects millions of individuals worldwide and results in a substantial burden to healthcare systems. Although it is established that CAD affects females differently than males, differences between the sexes are not routinely accounted for. Body mass index is a known risk factor for CAD. However, more accurate metrics of body fat, including waist-to-hip circumference ratio (WHR), could be more meaningful clinically. WHR exhibits sex differences due to sex hormones, differing effects at genetic risk loci, and other factors. It is unclear if WHR is a causal factor for CAD in one or both sexes, but this information will be crucial for improving heart health. Causal inference, however, can be challenging. Large-scale cohorts with genetic data allow for Mendelian randomization, which, given certain assumptions, tests whether there is a causal relationship between an exposure and the outcome using genetic variants. We conducted sex-specific, one-sample MR analyses using two-stage least-squares regression in the UK Biobank with genetic variants robustly associated with WHR. We found evidence of a causal relationship between WHR and CAD risk in females (OR [95% CI] = 1.16 [1.06-1.26]; p value = 7.5E-4), whereas in males, we did not find evidence of a causal relationship (OR [95% CI] = 1.40 [0.98-2.01]; p value = 0.063). Results were supported by two additional MR approaches (using a genetic risk score and two-sample MR using the inverse variance weighted approach). We encourage future work assessing sex-specific effects using causal inference techniques to better understand factors contributing to complex disease risk.

Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion.

Sensory neurons in the dorsal root ganglia (DRG) convey somatosensory and metabolic cues to the central nervous system and release substances from stimulated terminal endings in peripheral organs. Sex-biased variations driven by the sex chromosome complement (XX and XY) have been implicated in the sensory-islet crosstalk. However, the molecular underpinnings of these male-female differences are not known. Here, we aim to characterize the molecular repertoire and the secretome profile of the lower thoracic spinal sensory neurons and to identify molecules with sex-biased insulin sensing- and/or insulin secretion-modulating activity that are encoded independently of circulating gonadal sex hormones. We used transcriptomics and proteomics to uncover differentially expressed genes and secreted molecules in lower thoracic T5-12 DRG sensory neurons derived from sexually immature 3-week-old male and female C57BL/6J mice. Comparative transcriptome and proteome analyses revealed differential gene expression and protein secretion in DRG neurons in males and females. The transcriptome analysis identified, among others, higher insulin signaling/sensing capabilities in female DRG neurons; secretome screening uncovered several sex-specific candidate molecules with potential regulatory functions in pancreatic ß cells. Together, these data suggest a putative role of sensory interoception of insulin in the DRG-islet crosstalk with implications in sensory feedback loops in the regulation of ß-cell activity in a sex-biased manner. Finally, we provide a valuable resource of molecular and secretory targets that can be leveraged for understanding insulin interoception and insulin secretion and inform the development of novel studies/approaches to fathom the role of the sensory-islet axis in the regulation of energy balance in males and females.

A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics.

Epigenetic sex differences and their resulting implications for human health have been studied for about a decade. The objective of this paper is to use permutation-based inference and a new ranked-based test statistic to identify sex-based epigenetic differences in the human DNA methylome. In particular, we examine whether we could identify separations between the female and male distributions of DNA methylation across hundred of thousands CpG sites in two independent cohorts, the Swedish Adoption Twin study and the Lamarck study. Based on Fisherian p-values, we set a threshold for methylation differences "worth further scrutiny". At this threshold, we were able to confirm previously-found CpG sites that stratify with respect to sex. These CpG sites with sex differences in DNA methylation should be further investigated for their possible contribution to various physiological and pathological functions in the human body. We followed-up our statistical analyses with a literature review in order to inform the proposed disease implications for the loci we uncovered.

Sexual selection in seaweed? Testing Bateman's principles in the red alga Gracilaria gracilis.

In anisogamous species, sexual selection is expected to be stronger in males. Bateman's principles state that the variance in (i) reproductive and (ii) mating success is greater for males, and (iii) the relationship between reproductive success and mating success (the Bateman gradient) is also stronger for males than for females. Sexual selection, based on Bateman's principles, has been demonstrated in animals and some angiosperms, but never in a seaweed. Here we focus on the oogamous haploid-diploid rhodophyte Gracilaria gracilis in which previous studies have shown evidence for non-random mating, suggesting the existence of male-male competition and female choice. We estimated mating and reproductive success using paternity analyses in a natural population where up to 92% of fertilizations occurred between partners of that population. The results show that the variance in mating success is significantly greater in males than in females and that the Bateman gradient is positive only in males. Distance to female partners also explains a minor part of the variance in male mating success. Although there is no evidence for sexual dimorphism, our study supports the hypothesis that sexual selection occurs in G. gracilis, probably on male traits, even if we cannot observe, characterize or quantify them yet.

Sex Differences in Neurovascular Control: Implications for Obstructive Sleep Apnea.

Patients with obstructive sleep apnea (OSA) have a heightened risk of developing cardiovascular diseases, namely hypertension. While seminal evidence indicates a causal role for sympathetic nerve activity in the hypertensive phenotype commonly observed in patients with OSA, no studies have investigated potential sex differences in the sympathetic regulation of blood pressure in this population. Supporting this exploration are large-scale observational data, as well as controlled interventional studies in healthy adults, indicating that sleep disruption increases blood pressure to a greater extent in females relative to males. Furthermore, females with severe OSA demonstrate a more pronounced hypoxic burden (i.e., disease severity) during rapid eye movement sleep when sympathetic nerve activity is greatest. These findings would suggest that females are at greater risk for the hemodynamic consequences of OSA and related sleep disruption. Accordingly, the purpose of this review is three-fold: (1) to review the literature linking sympathetic nerve activity to hypertension in OSA, (2) to highlight recent experimental data supporting the hypothesis of sex differences in the regulation of sympathetic nerve activity in OSA, and (3) to discuss the potential sex differences in peripheral adrenergic signaling that may contribute to, or offset, cardiovascular risk in patients with OSA.

Sex differences in distribution and identity of aromatase gene expressing cells in the young adult rat brain.

BACKGROUND: Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene (Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene. METHODS: Cyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied. RESULTS: In the male brain, the highest percentage of Cyp19a1+ cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1+ cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1+ cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3, suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1+ cells. CONCLUSIONS: Females show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.

It is known that there are differences in the way males and females are mentally affected. These have been in part attributed to the effect of sex hormones, such as estrogen and testosterone. Within the framework of sex-specific medicine, it is therefore important to understand the biological substrates of sex-specific systems in the brain that are involved in any of these differences. The present study investigated the enzyme responsible for the synthesis of estrogen in the brain, to identify where it is expressed in the brain and to characterize the cells in which it is expressed. To this end, female and male young adult rats were studied. Brain slices including regions of relevance to, among others, emotion processing, were analyzed using fluorescent probes for the genes of interest and visualized using microscopy. Automated cell counting illustrated sex differences, with males displaying greater expression of the aromatase gene, compared with females, in several regions. The aromatase gene was expressed together with genes for the major inhibitory and excitatory neurotransmitters.

Kinking, coiling and diameters of vertebral artery first segment and their relationships to sex and side.

INTRODUCTION: Recent information on tortuosity in the prevertebral (V1) segment of the vertebral artery is based on case reports rather than systematic data on its presence, types, diameters, and sex- or left-right differences.

Sex differences in serum pigment epithelium-derived factor in healthy individuals.

To investigate sexual dimorphism of serum pigment epithelium-derived factor (PEDF) and its influencing factors in healthy individuals. A total of 162 healthy people (69 males, 93 females) who underwent health examinations in our department were selected. Serum PEDF, estradiol and other metabolic indices were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell function (HOMA-ß) were calculated to evaluate insulin resistance and ß-cell function, respectively. Subjects were divided into < 50 years and ≥ 50 years groups to explore the sexual dimorphism of serum PEDF in different age groups. We found no statistically significant difference in serum PEDF levels between men and women in total. However, in the group of subjects under 50 years old, men had significantly higher PEDF levels than women (9.32 ±â€…2.07 µg/mL vs 8.24 ±â€…2.29 µg/mL, P < .05), and no sex difference was found in the ≥ 50 years group. In women, serum PEDF levels were significantly higher in subjects aged 50 years and over than in those younger than 50 years of age (9.56 ±â€…3.05 µg/mL vs 8.25 ±â€…2.30 µg/mL, P < .05). In men, there was no significant difference in serum PEDF levels between the 2 age groups. In women, correlation analysis showed that serum PEDF levels were significantly correlated with body mass index, waist circumference, diastolic blood pressure (DBP), 2-h postprandial glucose, fasting and 2-h postprandial insulin, HOMA-ß, HOMA-IR, aminotransferase, triacylglycerol, and estradiol. Elevated triacylglycerol and aminotransferase and decreased estradiol were significant predictors of increased PEDF concentrations in women. There is sexual dimorphism in circulating PEDF levels, which may be related to estrogen status.

Sex differences in mortality among children, adolescents, and young people aged 0-24 years: a systematic assessment of national, regional, and global trends from 1990 to 2021.

BACKGROUND: Differences in mortality exist between sexes because of biological, genetic, and social factors. Sex differentials are well documented in children younger than 5 years but have not been systematically examined for ages 5-24 years. We aimed to estimate the sex ratio of mortality from birth to age 24 years and reconstruct trends in sex-specific mortality between 1990 and 2021 for 200 countries, major regions, and the world. METHODS: We compiled comprehensive databases on the mortality sex ratio (ratio of male to female mortality rates) for individuals aged 0-4 years, 5-14 years, and 15-24 years. The databases contain mortality rates from death registration systems, full birth and sibling histories from surveys, and reports on household deaths in censuses. We modelled the sex ratio of age-specific mortality as a function of the mortality in both sexes using Bayesian hierarchical time-series models. We report the levels and trends of sex ratios and estimate the expected female mortality and excess female mortality rates (the difference between the estimated female mortality and the expected female mortality) to identify countries with outlying sex ratios. FINDINGS: Globally, the mortality sex ratio was 1·13 (ie, boys were more likely to die than girls of the same age) for ages 0-4 years (90% uncertainty interval 1·11 to 1·15) in 2021. This ratio increased with age to 1·16 (1·12 to 1·20) for 5-14 years, reaching 1·65 for 15-24 years (1·52 to 1·75). In all age groups, the global sex ratio of mortality increased between 1990 and 2021, driven by faster declines in female mortality. In 2021, the probability of a newborn male reaching age 25 years was 94·1% (93·7 to 94·4), compared with 95·1% for a newborn female (94·7 to 95·3). We found a disadvantage of females versus males (compared with countries with similar total mortality) in 2021 in five countries for ages 0-4 years (Algeria, Bangladesh, Egypt, India, and Iran), one country (Suriname) for ages 5-14 years, and 13 countries for ages 15-24 years (including Bangladesh and India). We found the reverse pattern (disadvantage of males vs females compared with countries of similar total mortality) in one country in ages 0-4 years (Vietnam) and eight countries in ages 15-24 years (including Brazil and Mexico). Globally, the number of excess female deaths from birth to age 24 years was 86 563 (-6059 to 164 000) in 2021, down from 544 636 (453 982 to 633 265) in 1990. INTERPRETATION: The global sex ratio of mortality for all age groups in the first 25 years of life increased between 1990 and 2021. Targeted interventions should focus on countries with outlying sex ratios of mortality to reduce disparities due to discrimination in health care, nutrition, and violence. FUNDING: The Bill & Melinda Gates Foundation, US Agency for International Development, and King Abdullah University of Science and Technology.

Sex differences in renal cell carcinoma: a single-cell analysis reveals exhausted CD8+ T-cells highly infiltrated in males.

BACKGROUND: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments. RESULTS: Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8+ T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. CONCLUSIONS: Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients.

Genotypic sex shapes maternal care in the African pygmy mouse, Mus minutoides.

Sexually dimorphic behaviours, such as parental care, have long been thought to be mainly driven by gonadal hormones. In the past two decades, a few studies have challenged this view, highlighting the direct influence of the sex chromosome complement (XX versus XY or ZZ versus ZW). The African pygmy mouse, Mus minutoides, is a wild mouse species with naturally occurring XY sex reversal induced by a third, feminizing X* chromosome, leading to three female genotypes: XX, XX* and X*Y. Here, we show that sex reversal in X*Y females shapes a divergent maternal care strategy (maternal aggression, pup retrieval and nesting behaviours) from both XX and XX* females. Although neuroanatomical investigations were inconclusive, we show that the dopaminergic system in the anteroventral periventricular nucleus of the hypothalamus is worth investigating further as it may support differences in pup retrieval behaviour between females. Combining behaviours and neurobiology in a rodent subject to natural selection, we evaluate potential candidates for the neural basis of maternal behaviours and strengthen the underestimated role of the sex chromosomes in shaping sex differences in brain and behaviours. All things considered, we further highlight the emergence of a third sexual phenotype, challenging the binary view of phenotypic sexes.

Sex differences in acute health service contact after release from prison in Australia: a data linkage study.

OBJECTIVES: Women released from prison typically experience worse health outcomes than their male counterparts. We examined sex differences in the patterns, characteristics, and predictors of acute health service contact (AHSC) (i.e. ambulance and/or emergency department use) after release from prison. STUDY DESIGN: Data linkage study. METHODS: Baseline survey data from 1307 adults (21% women) within six weeks of expected release from prisons in Queensland, Australia (2008-2010) were linked prospectively with state-wide ambulance and emergency department, correctional, mental health, and death records. Crude and adjusted incidence rates and incidence rate ratios of AHSC were calculated overall and by sex. An Andersen-Gill model was fit to examine whether sex predicted AHSC. The interaction effect between sex and each model covariate was tested. RESULTS: The crude incidence rates of AHSC after release from prison were 1.4 (95% confidence interval [CI]: 1.3-1.5) and 1·1 (95%CI: 1.1-1.2) per person-year for women and men, respectively. The relationship between perceived physical health-related functioning at the baseline and AHSC was modified by sex (P = 0·039). The relationship between perceived health-related functioning and AHSC also differed among women. Compared to women who perceived their physical health as fair or good at the baseline, women who perceived their physical health as poor were at greater risk of AHSC (hazard ratio = 2.4, 95%CI: 1.4-3·9, P = 0.001) after release from prison. CONCLUSIONS: Among people released from prison, women's and men's AHSC differs depending on how they perceive their own physical health. The specific needs of women and men must be considered in transitional support policy and planning to improve their health outcomes.

Assessing the roles of shape prototypicality and sexual dimorphism in ratings of the trustworthiness of faces.

Perceptions of the trustworthiness of faces predict important social outcomes, including economic exchange and criminal sentencing decisions. However, the specific facial characteristics that drive trustworthiness perceptions remain poorly understood. Here we investigated this issue by exploring possible relationships between ratings of the trustworthiness of face images and objective assessments of two aspects of face shape that researchers have previously argued are important for perceptions of trustworthiness: distinctiveness and sexual dimorphism. Here we report that faces with more distinctive shapes are rated as less trustworthy, but that sexual dimorphism of face shape is not significantly correlated with trustworthiness ratings. These results suggest that distinctiveness of face shape plays a more important role in trustworthiness perceptions than does sexual dimorphism and suggest that perceptions of trustworthiness may stem, at least in part, from the 'anomalous-is-bad' stereotype.

Sex Differences in HIV Infection.

Biological sex has wide-ranging impacts on HIV infection spanning differences in acquisition risk, the pathogenesis of untreated infection, impact of chronic treated disease and prospects for HIV eradication or functional cure. This chapter summarizes the scope of these differences and discusses several features of the immune response thought to contribute to the clinical outcomes.